A diverse array of compounds, including anthraquinones, acridines, cationic porphyrins, perylenes, thidium derivatives, fluorenones, pentacyclic acridinium salts, fluoroquinophenoxazines, and other specific miscellaneous polycyclic compounds, have been reported to stabilize G-quadruplex DNA. Most of these compounds have limited selectivity for G-quadruplex vs. duplex DNA.
Telomestatin is a natural product isolated from Streptomyces anulatus 3533-SV4 (Shinya et al., J. Am. Chem. Soc., 2001, 123, 1262-1263). At the time of its discovery, telomestatin was viewed as the most potent inhibitor of telomerase. In vitro, telomestatin stabilizes G-quadruplex vs. duplex DNA in a 70:1 ratio (Kim et al., Cancer Res., 2003, 63, 3247-3256). It has been suggested that telomestatin also inhibits telomerase function in vivo, since cells treated with the natural product exhibit a cellular senescence phenotype. Like telomere dysfunction, telomestatin activates the ATM signaling pathway. While the precise mechanism by which telomestatin interacts with a G-quadruplex has not been definitively elucidated, telomestatin does suppress the plating efficiency of K62 leukemia cells but has a much lesser effect on burst-forming units-erythrocyte (BFU-E) and colony-forming units-granulocyte/macrophage (CFU-GM) from natural bone marrow CD34-positive cells (Tauchi et al., Oncogene, 2003, 22, 5338-5347).

The anticancer potential of telomestatin has been reported to be associated with its telomerase inhibitory activity (IC50 5 nM) and in its ability to enhance apoptosis. Telomestatin has been evaluated for cytotoxicity in the human neuroblastoma cell lines SK-N-AS, LAN5, WAC2, and LAN1 with IC50 values of 0.8, 2.5, 3.2, and 4.0 μM respectively (Binz et al., Eur. J. Cancer, 2005, 41, 2873-2881) and in the human pancreatic carcinoma MiaPaCa with an IC50 value of 0.5 μM (Liu et al., Nucleosides, Nucleotides, and Nucleic Acids, 2005, 24, 1801-1815). The in vivo activity of telomestatin has also been evaluated in xenographs of acute human leukemia (U937) cells in mice (Tauchi et al., Oncogene, 2006, 25, 5719-5725).
Another macrocyclic polyoxazole, YM-216391 isolated from Streptomyces nobilis is active against the human breast cancer cell lines HBC-4, BSY-1, HBC-5, MCF-7, and MDA-MB-231 with GI50 values ranging from 15-33 nM (Sohda, K-y., et al., J. Antibiotics, 2005, 58, 27-31 and Sohda, K-y., et al., Hiramoto, M., Suzumura, K-i., Takebayashi, Y., Suzuki, K-i., Tanaka, A. J. Antibiotics, 2005, 58, 32-36).
The mechanism of action of YM-216391 has not yet been elucidated.
Certain specific compounds have also been reported to stabilize G-quadruplex DNA and RNA (Barbieri, C., Nucleic Acids Research, 2007, 35(10) 3272-3286).
International Patent Applications Publication Numbers WO2007/127173, WO2009/018551, and WO2009/018549 disclose compounds that are reported to stabilize G-quadruplex DNA. However, the commercial development of these compounds may be less desirable due to the difficult synthetic processes and low yields associated with their preparation.
Currently, there is a need for novel therapeutic agents and therapeutic methods that are useful for treating diseases such as cancer. Such agents may have improved binding affinity for G-quadruplex DNA and/or they may have advantageous drug-like properties. Additionally, there is a need for compounds that stabilize G-quadruplex DNA, which can be prepared in commercially useful quantities using commercially viable starting materials and processes.